In our Preliminary Studies, we found that DDR2, the discoidin domain receptor 2 tyrosine kinase gene, is somatically mutated in 3 to 4% of lung squamous cell carcinomas (lung SCC). Knock-down of DDR2 kills lung SCC cells bearing DDR2 mutations. Furthermore, treatment of DDR2-mutant lung SCC cells with the tyrosine kinase inhibitor dasatinib significantiy decreases cell proliferation; the effects of dasatinib are rescued by over-expression of DDR2 bearing the dasatinib-resistant T654M gatekeeper mutation. We now aim to develop DDR2 further as a therapeutic target for lung SCC. Our specific aims are to work with the other Projects and the shared resource Cores as follows: -Specific Aim 1. We will characterize the oncogenic potential of tumor-derived DDR2 mutants in the basal epithelium of the lung using cellular and animal model systems. We will work with Core C (Animal) to generate transgenic mouse models for lung basal epithelium-specific expression of DDR2 mutants and assay for tumor formation. We will also express DDR2 mutant mRNA in basal lung epithelium and test for oncogenic effects. These animal and cellular models will be used to assess the impact of disruption of DDR2 function both by genetic modification and by small molecule inhibitors. -Specific Aim 2. We will evaluate mechanisms of resistance to the DDR2 inhibitor, dasatinib, in squamous lung cancer models. To study c/s resistance to dasatinib, we will engineer and/or select for dasatinib resistance alleles in DDR2 and test their sensitivities to dasatinib and other kinase inhibitors. In addition, we will screen for trans resistance by ectopic expression of open reading frame libraries. -Specific Aim 3. Develop potent and selective inhibitors of DDR2 using biochemical and cellular assays, their effects. We will collaborate with Core A (Chemistry) and Core B (Structure) to optimize lead compounds identified by Core A as mutant-specific inhibitors of DDR2 with greater DDR2 kinase specificity relative to dasatinib. These optimized inhibitors will be tested in both lung SCC-derived cell lines and in the cellular and animal model systems developed in Aim 1, including models engineered to be resistant to dasatinib. Through these efforts, this project will advance the development of DDR2 inhibitors as potential treatments for squamous cell carcinomas of the lung.